title: Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury.
abstract: Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.
authors.affiliation: Division of Nephrology and Hypertension and Institute for Pathology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.forename: Jan Hinrich
authors.initials: JH
authors.lastname: Bräsen
authors.forename: Maurice
authors.initials: M
authors.lastname: Darding
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Jin
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.forename: Jan-Ole
authors.initials: JO
authors.lastname: Heller
authors.forename: Federica
authors.initials: F
authors.lastname: De Zen
authors.forename: Ricardo
authors.initials: R
authors.lastname: Weinlich
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: Stefan
authors.initials: S
authors.lastname: Krautwald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005838:Genotype; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis / Q000209:etiology / Q000503:physiopathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D017931:DNA Primers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D007770:L-Lactate Dehydrogenase; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D021983:Cyclophilins
keywords: RIP1; RIP3; apoptosis; programmed necrosis